Synthesis of pyridine-fused ring systems from β-chloroacroleins: A comparison of three different pathways

Article abstract of DOI:10.1055/s-2003-38081

Three different pathways for the access of pyridine-fused ring systems are described: 1) a Sonogashira coupling of β-chloroacroleins followed by cyclization of the corresponding imines; 2) the same coupling reaction followed by cyclization of the corresponding oximes; and 3) a palladium-catalyzed iminoannulation of internal alkynes.

Full text of DOI:10.1055/s-2003-38081

PAPER
717
Synthesis of Pyridine-Fused Ring Systems from -Chloroacroleins:
A Comparison of Three Different Pathways
Synthesis of
P
t
yridine
é
-Fuse
d
Rin
p
System
s
hanie Hesse, Gilbert Kirsch*
Laboratoire d’Ingénierie Moléculaire et Biochimie Pharmacologique, Faculté des Sciences, Ile du Saulcy, 57045 Metz Cedex, France
E-mail: kirsch@sciences.univ-metz.fr
Received 17 December 2002; revised 18 January 2003
scribed by Sonogashira et al.9 in 1975. Sonogashira cou-
pling is usually carried out in the presence of catalytic
palladium(II) complex and copper(I) iodide in an amine as
solvent. Under these conditions, it is necessary to exclude
Abstract: Three different pathways for the access of pyridine-fused
ring systems are described: 1) a Sonogashira coupling of β-chloro-
acroleins followed by cyclization of the corresponding imines; 2)
the same coupling reaction followed by cyclization of the corre-
sponding oximes; and 3) a palladium-catalyzed iminoannulation of oxygen from the reaction media to prevent the oxidative
internal alkynes.
homocoupling of the alkyne. Indeed, the formation of
such a product decreases the reaction yield and makes the
purification difficult. This is due to the similar polarities
of the homocoupled byproduct, cross-coupled product
and the unreacted halogen derivative which make their
separation by column chromatography a difficult task.
Key words: β-chloroacroleins, Sonogashira coupling, heteroannu-
lation, imines
Annulation processes constitute a powerful methodology
for speedy synthesis of complicated heterocycles. This
method has been widely used for the synthesis of indoles,1
benzofurans,2 benzopyrans,2 isocoumarins,2,3 and
pyrones3,4 (Scheme 1).
Thus, in a first attempt, our reactions were carried under
argon to prevent side reactions, in the presence of 2.5
mol% of palladium complex and 3 mol% of copper iodide
(Procedure A). They were almost complete after 18 hours
at 80 °C and we observed good yields of the coupled prod-
ucts 1, although the formation of few homocoupled
byproducts was noticed. We thus investigated other con-
ditions and especially that of Jeffery’s10 as they have car-
ried out Suzuki coupling of the same β-chloroacroleins in
good yields under mild conditions.8 Reactions were per-
formed in the presence of tetrabutylammonium bromide,
triethylamine and palladium catalyst in water–acetonitrile
media (Procedure B). Two hours at room temperature are
sufficient to obtain the coupled products 1 in comparable
yield to the former method (Scheme 2 and Table 1).
R1
R2
XH
X
R2
cat Pd(0), base
I
R1
X = NR, O, CO, CO2H
R1, R2 = alkyl, aryl, alkenyl
Scheme 1
Since few years, Larock and co-workers have been inter-
ested in the synthesis of isoquinolines and pyridines.5 For
this purpose, they have developed a palladium-catalyzed
iminoannulation of internal alkynes6 as well as a three-
step sequence involving palladium/copper-catalyzed cou-
pling of terminal alkynes and subsequent cyclization of
acetylenes and unsaturated imines.7 However to our
knowledge, they always studied iodide or bromide deriv-
atives. As we were particularly interested in the behaviour
of β-chloroacroleins in cross-coupling reaction,8 we de-
cided to investigate their reactivity toward Sonogashira
coupling and iminoannulation of internal alkynes.
Access to Pyridine-Fused Ring Systems via Cycliza-
tion of Iminoalkynes
We then synthesized the corresponding iminoalkynes 2a–
d by reaction with tert-butylamine at room temperature.
They are obtained in excellent yields and did not need fur-
ther purification. The next step of our synthesis consists in
the cyclization of iminoalkynes. Larock and co-workers
have tried several electrophiles and have shown that cata-
lytic amounts of silver nitrate allowed the ring closure of
iminoalkynes under mild conditions.7a We decided to ap-
ply those conditions to our products and thus obtained the
isoquinoline and pyridine derivatives 3a–d (Scheme 2
and Table 1).
Sonogashira Coupling of -Chloroacroleins
One of the most powerful methods for the preparation of
conjugated enynes is the palladium-catalyzed coupling of
terminal alkynes with alkenyl halides which was first de-
Synthesis 2003, No. 5, Print: 01 04 2003.
Art Id.1437-210X,E;2003,0,05,0717,0722,ftx,en;Z15602SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

718
S. Hesse, G. Kirsch
PAPER
Scheme 3
Scheme 2
Table 1 Access to Pyridine-Fused Ring Systems via Imines
Entry
R
X
Coupled Product Imine
Product
1 (%)a
A 90
A 82
2 (%)
3 (%)a
a
b
c
H
CH2
CH2
O
80
47
55
62
Me
H
96
A 59
B 85
95
Scheme 4
d
H
S
A 82
B 78
95
36
Access to Pyridine-Fused Ring Systems via Iminoan-
nulation of Internal Alkynes
a Isolated yield after column chromatographic purification. A and B =
Procedure A and Procedure B.
As the former three-step sequence gave satisfactory re-
sults, we were encouraged to investigate the iminoannula-
tion of internal alkynes. Larock5 has shown that only tert-
butylimines may undergo iminoannulation while meth-
yl-, isopropyl-, allyl- and benzylimines did not allow the
formation of the desired heterocyclic products. Imines
5a–c were synthesized from β-chloroacroleins using the
same procedure as above. Iminoannulation of these imi-
nes with an internal alkyne was carried out in the presence
of 5 mol% of palladium acetate and 10 mol% of triphe-
nylphosphine in DMF during 48 hours at 100 °C. Com-
pounds 5a and 5c led to only one product whereas 5b
furnished two isomers (Scheme 5 and Table 2).
Access to Pyridine-Fused Ring Systems via Cycliza-
tion of Oximes
In his synthesis of (R)-(–)-pyrindolols,11 Hibino described
the thermal cyclization of 3-alkynylindol-2-aldoximes to
construct β-carboline N-oxides. These compounds were
then heated with acetic anhydride to afford 1-hydroxy-β-
carbolines (Scheme 3)
We also decided to study this pathway. Treatment of 1a,b
with hydroxylamine furnished the corresponding oximes
4a,b in 91% and 98% yields, respectively. However, ther-
mal cyclization of 4a,b did not lead to N-oxide com-
pounds, instead pyridine-fused ring systems 3a,b were
isolated (Scheme 4).
In conclusion, β-chloroacroleins gave satisfying results in
Sonogashira coupling and allowed the formation of sever-
al pyridine-fused ring systems. These chloride derivatives
also underwent iminoannulation but the yields were low.
Synthesis 2003, No. 5, 717–722 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of Pyridine-Fused Ring Systems
719
argon. In another round-bottom flask, a mixture of the alkyne (2.1
mmol), the appropriate β-chloroacrolein (2 mmol), Bu4NBr (2
mmol) and Et3N (0.7 mL, 5 mmol) in H2O–MeCN (1:10, 5 mL) was
prepared. The former catalytic system was added to this solution
and the reaction mixture was stirred at r.t. until the starting β-chlo-
roacrolein had disappeared. The mixture was then hydrolyzed by
H2O (10 mL) and extracted with Et2O (3 × 30 mL). Removal of the
solvent and purification by column chromatography gave the ex-
pected product.
1-Phenylethynyl-3,4-dihydronaphthalene-2-carboxaldehyde
(1a)
Purified by column chromatography on silica gel using CH2Cl2 as
eluent; brown solid; mp 83–84 °C.
IR (CH2Cl2): 2205, 1663 cm–1.
1H NMR (250 MHz, CDCl3): δ = 2.63–2.69 (m, 2 H), 2.84–2.90 (m,
2 H), 7.24–7.26 (m, 1 H), 7.35–7.43 (m, 5 H), 7.59–7.63 (m, 2 H),
7.93–7.96 (m, 1 H), 10.53 (s, 1 H, CHO).
13C NMR (62.9 MHz, CDCl3): δ = 19.94 (CH2), 26.77 (CH2), 82.98
(C-1′), 101.08 (C-2′), 122.11 (C-3′), 126.98 (CH), 127.25 (CH),
127.84 (CH), 128.58 (CH), 129.42 (CH), 130.72 (CH), 131.80
(CH), 132.24 (C), 135.95 (C), 137.67 (C), 140.34 (C), 192.21
(CHO).
Scheme 5
Table 2 Access to Pyridine-Fused Ring Systems via Iminoannula-
tion
Entry X
Imine Product
5 (%)
Yield 6
(%)a
a
CH2 95
47
Ph
Ph
5,7-Dimethyl-1-phenylethynyl-3,4-dihydronaphthalene-2-car-
boxaldehyde (1b)
Purified by column chromatography on silica gel using CH2Cl2–cy-
clohexane (1:1) as eluent; orange solid; mp 81–82 °C.
Me
N
N
IR (CH2Cl2): 2199, 1660 cm–1.
b
O
S
98
28/20
Me
1H NMR (250 MHz, CDCl3): δ = 2.31 (s, 3 H), 2.39 (s, 3 H), 2.60–
2.66 (m, 2 H), 2.74–2.80 (m, 2 H), 7.09 (s, 1 H), 7.41–7.44 (m, 3 H),
7.60–7.64 (m, 3 H), 10.52 (s, 1 H, CHO).
Me
Ph
N
13C NMR (62.9 MHz, CDCl3): δ = 19.70 (CH3), 19.82 (CH2), 21.07
(CH3), 22.52 (CH2), 83.42 (C-1′), 100.82 (C-2′), 122.28 (C-3′),
125.93 (CH), 128.60 (CH), 129.34 (CH), 131.77 (CH), 132.03 (C),
133.06 (C), 133.66 (CH), 135.21 (C), 135.71 (C), 136.48 (C),
139.86 (C), 192.40 (CHO).
O
O
c
96
10
Ph
Me
N
4-Phenylethynyl-2H-chromene-3-carboxaldehyde (1c)
Purified by column chromatography on silica gel using CH2Cl2 as
eluent; orange solid; mp 127–128 °C.
S
IR (CH2Cl2): 2206, 1653 cm–1.
a Isolated yield after column chromatographic purification.
1H NMR (250 MHz, CDCl3): δ = 5.05 (s, 2 H, H-2), 6.93 (d, 1 H,
J = 8.3 Hz), 7.07 (m, 1 H), 7.35 (d, 1 H, J = 7.8 Hz), 7.40–7.45 (m,
3 H), 7.62 (dd, 2 H, J = 7.2, 2.2 Hz), 7.78 (d, 1 H, J = 7.8 Hz), 10.30
(s, 1 H, CHO).
13C NMR (62.9 MHz, CDCl3): δ = 62.95 (CH2), 80.75 (C-1′),
102.40 (C-2′), 116.59 (CH), 120.63 (C), 121.34 (C), 121.88 (CH),
127.51 (CH), 128.52 (CH), 129.78 (CH), 131.62 (C), 131.87 (CH),
132.89 (C), 133.17 (CH), 155.63 (C), 189.05 (CHO).
PdCl2 and CuI were purchased from Aldrich, Ph3P from Fluka and
phenylacetylene from Lancaster. β-Chloroacroleins were prepared
according to the literature procedure.12 Melting points were deter-
mined on a Stuart SMP3 apparatus and are uncorrected. 1H and 13
C
spectra were recorded on a AC Bruker 250 MHz spectrometer in
CDCl3. IR spectra were obtained on a Bruker TENSOR 27 spec-
trometer.
4-Phenylethynyl-2H-thiochromene-3-carboxaldehyde (1d)
Purified by column chromatography on silica gel using CH2Cl2–cy-
clohexane (1:1 2:1) as eluent; yellow solid; mp 84 °C.
IR (CH2Cl2): 2204, 1662 cm–1.
1H NMR (250 MHz, CDCl3): δ = 3.72 (s, 2 H, H-2), 7.29–7.36 (m,
3 H), 7.42–7.44 (m, 3 H), 7.58–7.61 (m, 2 H), 7.98–8.02 (m, 1 H),
10.47 (s, 1 H, CHO).
13C NMR (62.9 MHz, CDCl3): δ = 22.01 (CH2), 83.16 (C-1′),
102.17 (C-2′), 121.70 (C), 125.98 (CH), 127.75 (CH), 128.63 (CH),
129.55 (CH), 129.72 (CH), 130.93 (CH), 131.81 (CH), 132.15 (C),
133.80 (C), 136.06 (C), 136.41 (C), 190.59 (CHO).
Sonogashira Coupling; General Procedures
Procedure A: A solution of PdCl2 (2.5mol%) and Ph3P (5mol%) in
Et3N (4 mL) was flushed with argon. The appropriate β-chloroac-
rolein (2 mmol, 1 equiv) was added, then CuI (3 mol%) and finally,
phenylacetylene (2.4 mmol, 1.2 equiv) diluted with Et3N (4 mL).
The reaction mixture was stirred for 18 h at 80 °C. After cooling to
r.t., the Et3N HCl was filtered and washed with Et2O. The resulting
filtrate was concentrated under reduced pressure and the residue
was purified by column chromatography on silica gel.
Procedure B: A solution of Pd(OAc)2 (0.2 mmol, 8 mol%) and Ph3P
(0.4 mmol, 16 mol%) in H2O–MeCN (1:10, 5 mL) was stirred under
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S. Hesse, G. Kirsch
PAPER
Imines 2, 5; General Procedure
tert-Butyl-(1-chloro-3,4-dihydronaphthalene-2-ylmethylene)-
To a solution of aldehyde 1a–d (3.5 mmol, 1 equiv) in benzene (3
mL) was added Na2SO4 (1 g). After cooling the reaction mixture to
0 °C, a solution of tert-butylamine (3.8 mmol, 1.1 equiv) in benzene
(0.5 mL) was added dropwise. The mixture was stirred at r.t. over-
night. Na2SO4 was filtered off, washed with CH2Cl2, and the filtrate
was concentrated under reduced pressure. The residue was pure
enough to be used in the next step.
amine (5a)
Brown oil.
IR (CH2Cl2): 2968, 1669, 1601 cm–1.
1H NMR (250 MHz, CDCl3): δ = 1.29 (s, 9 H, t-C4H9), 2.82 (s, 4 H),
7.25–7.29 (m, 3 H), 7.73–7.77 (m, 1 H), 8.67 (s, 1 H).
13C NMR (62.9 MHz, CDCl3): δ = 24.38 (CH2), 27.94 (CH2), 30.35
(CH3), 58.38 (C), 125.47 (CH), 127.09 (CH), 127.69 (CH), 129.44
(CH), 133.45 (C), 133.63 (C), 135.40 (C), 138.41 (C), 154.46
(CH=N).
tert-Butyl-(1-phenylethynyl-3,4-dihydronaphthalene-2-ylmeth-
ylene)amine (2a)
Brown oil.
IR (CH2Cl2): 2967, 2204, 1663, 1610 cm–1.
tert-Butyl-(4-chloro-2H-chromene-3-ylmethylene)amine (5b)
Yellow oil.
IR (CH2Cl2): 2969, 1601 cm–1.
1H NMR (250 MHz, CDCl3): δ = 1.25 (s, 9 H, t-C4H9), 5.13 (s, 2 H,
H-2), 6.89 (d, 1 H, J = 8.1 Hz), 6.97–7.03 (m, 1 H), 7.22–7.28 (m,
1 H), 7.58 (dd, 1 H, J = 7.8, 1.3 Hz), 8.44 (s, 1 H).
13C NMR (62.9 MHz, CDCl3): δ = 30.08 (CH3), 58.55 (C), 66.75
(CH2), 116.44 (CH), 121.95 (CH), 121.98 (C), 125.65 (CH), 126.50
(C), 131.69 (CH), 132.09 (C), 151.23 (CH=N), 156.02 (C).
1H NMR (250 MHz, CDCl3): δ = 1.33 (s, 9 H, t-C4H9), 2.84 (s, 4 H),
7.20–7.24 (m, 1 H), 7.28–7.32 (m, 2 H), 7.39–7.44 (m, 3 H), 7.57–
7.60 (m, 2 H), 7.84 (d, 1 H, J = 7.0 Hz), 8.89 (s, 1 H).
13C NMR (62.9 MHz, CDCl3): δ = 22.34 (CH2), 27.16 (CH2), 29.89
(CH3), 57.78 (C), 84.75 (C-1′), 98.55 (C-2′), 125.44 (C-3′), 125.98
(CH), 126.57 (CH), 127.37 (CH), 127.39 (CH), 128.47 (CH),
128.53 (CH), 131.45 (CH), 133.21 (C), 136.68 (C), 137.67 (C),
142.73 (C), 156.07 (CH=N).
tert-Butyl-(5,7-dimethyl-1-phenylethynyl-3,4-dihydronaphtha-
lene-2-ylmethylene)amine (2b)
Brown oil.
tert-Butyl-(4-chloro-2H-thiochromene-3-ylmethylene)amine
(5c)
Brown oil.
IR (CH2Cl2): 2968, 2197, 1662 cm–1.
IR (CH2Cl2): 2968, 1668, 1585 cm–1.
1H NMR (250 MHz, CDCl3): δ = 1.33 (s, 9 H, t-C4H9), 2.31 (s, 3 H),
2.37 (s, 3 H), 2.78 (s, 4 H), 6.99 (s, 1 H, H-6), 7.38–7.43 (m, 3 H),
7.54–7.60 (m, 3 H), 8.89 (s, CH=N)
1H NMR (250 MHz, CDCl3): δ = 1.29 (s, 9 H, t-C4H9), 3.94 (s, 2 H,
H-2), 7.19–7.23 (m, 2 H), 7.32–7.37 (m, 1 H), 7.79–7.82 (m, 1 H),
8.60 (s, 1 H).
13C NMR (62.9 MHz, CDCl3): δ = 19.55 (CH3), 21.11 (CH3), 22.21
(CH2), 22.84 (CH2), 29.94 (CH3), 57.74 (C), 85.24 (C-1′), 98.29 (C-
2′), 123.37 (C-3′), 124.76 (CH), 125.84 (C), 128.45 (CH), 128.48
(CH), 131.42 (CH), 131.45 (CH), 131.97 (C), 132.96 (C), 134.66
(C), 135.22 (C), 142.25 (C), 156.22 (CH=N)
13C NMR (62.9 MHz, CDCl3): δ = 25.48 (CH2), 29.73 (CH3), 58.06
(C), 125.57 (CH), 127.20 (CH), 127.51 (CH), 128.34 (C), 129.20
(CH), 132.72 (C), 135.66 (C), 135.78 (C), 152.75 (CH=N).
Cyclization of Imines 2a–d and 3a–d; General Procedure
To a suspension of AgNO3 (0.1 mmol, 10 mol%) in CHCl3 (20 mL)
under argon was added dropwise a solution of imine 2a–d (1 mmol)
in CHCl3 (8 mL). The reaction mixture was stirred for 48 h at 60 °C.
After cooling to r.t., the mixture was diluted with Et2O, the organic
phase was washed with brine, dried (MgSO4), filtered, and concen-
trated under reduced pressure. The residue was purified by chroma-
tography on silica gel.
tert-Butyl-(4-phenylethynyl-2H-chromene-3-ylmethylene)-
amine (2c)
Brown solid; mp 87–88 °C.
IR (CH2Cl2): 2968, 2206, 1599 cm–1.
1H NMR (250 MHz, CDCl3): δ = 1.34 (s, 9 H, t-C4H9), 5.23 (s, 2 H,
H-2), 6.94 (d, 1 H, J = 8.2 Hz), 7.05 (dd, 1 H, J = 7.4, 7.1 Hz), 7.27
(ddd, 1 H, J = 7.3, 8.2, 1.6 Hz), 7.39–7.45 (m, 3 H), 7.59–7.64 (m,
2 H), 7.73 (dd, 1 H, J = 7.8, 1.4 Hz), 8.70 (s, 1 H).
13C NMR (62.9 MHz, CDCl3): δ = 29.62 (CH3), 57.91 (C), 64.99
(CH2), 82.41 (C-1′), 99.33 (C-2′), 116.07 (CH), 121.41 (CH),
121.52 (C), 122.19 (C), 122.55 (C), 126.29 (CH), 128.49 (CH),
128.92 (CH), 130.60 (CH), 131.58 (CH), 134.50 (C), 152.68
(CH=N), 154.69 (C).
2-Phenyl-5,6-dihydrobenzo[f]isoquinoline (3a)
Purified by column chromatography on silica gel using CH2Cl2–
EtOAc (1:0 1:1) as eluent; brown oil.
IR (CH2Cl2): 3060, 2932, 1599 cm–1.
1H NMR (250 MHz, CDCl3): δ = 2.94 (s, 4 H), 7.30–7.55 (m, 6 H),
7.88–7.92 (m, 1 H), 8.03–8.06 (m, 3 H), 8.57 (s, 1 H, H-4).
13C NMR (62.9 MHz, CDCl3): δ = 25.11 (CH2), 28.51 (CH2),
114.52 (CH, C-1), 124.16 (CH), 126.80 (CH), 127.20 (CH), 128.54
(CH), 128.60 (CH), 128.66 (CH), 129.42 (CH), 130.32 (C), 132.15
(C), 138.21 (C), 139.81 (C), 142.37 (C), 148.91 (CH, C-4), 156.66
(C).
tert-Butyl-(4-phenylethynyl-2H-thiochromene-3-ylmethylene)-
amine (2d)
Brown oil.
IR (CH2Cl2): 2974, 2205, 1663, 1581 cm–1.
1H NMR (250 MHz, CDCl3): δ = 1.38 (s, 9 H, t-C4H9), 4.01 (s, 2 H,
H-2), 7.25–7.28 (m, 2 H), 7.39–7.45 (m, 4 H), 7.60–7.63 (m, 2 H),
7.97 (dd, 1 H, J = 6.4, 2.6 Hz), 8.91 (s, 1 H).
13C NMR (62.9 MHz, CDCl3): δ = 24.09 (CH2), 29.75 (CH3), 57.91
(C), 84.89 (C-1′), 99.16 (C-2′), 122.71 (C), 125.55 (CH), 126.08
(C), 127.32 (CH), 128.22 (CH), 128.46 (CH), 128.75 (CH), 128.78
(CH), 131.40 (CH), 132.89 (C), 134.28 (C), 136.79 (C), 154.60
(CH=N).
7,9-Dimethyl-2-phenyl-5,6-dihydrobenzo[f]isoquinoline (3b)
Purified by column chromatography on silica gel using CH2Cl2–
EtOAc (1:0 1:1) as eluent; orange oil.
IR (CH2Cl2): 3035, 2953, 1599 cm–1.
1H NMR (250 MHz, CDCl3): δ = 2.35 (s, 3 H), 2.42 (s, 3 H), 2.84
(s, 4 H), 7.09 (s, 1 H), 7.44–7.55 (m, 3 H), 7.59 (s, 1 H), 8.01 (s, 1
H), 8.08 (dd, 2 H, J = 7.0, 1.6 Hz), 8.57 (s, 1 H).
13C NMR (62.9 MHz, CDCl3): δ = 19.61 (CH3), 21.05 (CH3), 23.90
(CH2), 24.95 (CH2), 114.71 (CH, C-1), 122.58 (CH), 126.78 (CH),
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Synthesis of Pyridine-Fused Ring Systems
721
128.48 (CH), 128.58 (CH), 130.18 (C), 131.94 (C), 132.19 (CH),
133.66 (C), 135.64 (C), 135.88 (C), 139.91 (C), 142.82 (C), 148.60
(CH, C-4), 156.44 (C).
Cyclization of Oximes 4a,b to Isoquinolines 3a,b; General Pro-
cedure
A solution of oxime 4a,b (1 mmol) in o-dichlorobenzene (5 mL)
was heated at 165 °C for 25 min. After cooling to r.t., the reaction
mixture was concentrated under reduced pressure. The residue was
purified by column chromatography on silica gel using CH2Cl2 as
eluent to afford compounds 3a,b.
2-Phenyl-5H-chromeno[3,4-c]pyridine (3c)
Purified by column chromatography on silica gel using CH2Cl2–cy-
clohexane (8:2) to CH2Cl2–EtOAc (4:1) as eluent; brown oil.
1H NMR (250 MHz, CDCl3): δ = 5.17 (s, 2 H, H-5), 7.02–7.13 (m,
2 H), 7.31–7.38 (m, 2 H), 7.47–7.51 (m, 2 H), 7.82 (d, 1 H, J = 7.8
Hz), 7.93 (s, 1 H), 8.03 (d, 2 H, J = 7.3 Hz), 8.47 (s, 1 H).
13C NMR (62.9 MHz, CDCl3): δ = 65.74 (CH2O), 112.63 (CH, C-
7), 117.76 (CH, C-1), 120.59 (C), 122.28 (CH, C-9), 123.85 (CH),
124.32 (C), 126.86 (CH), 128.66 (CH), 128.96 (CH), 131.60 (CH),
138.20 (C), 139.32 (C), 145.57 (CH, C-4), 155.65 (C), 157.94 (C).
Iminoannulation of 5a–c to 6a–c; General Procedure
A solution of Pd(OAc)2 (5 mol%) and Ph3P (10 mol%) in DMF (10
mL) was flushed with argon. Na2CO3 (2 mmol, 1 equiv) was added
followed by a solution of alkyne (4 mmol, 2 equiv) in DMF (10
mL). Finally, a solution of imine 5 (2 mmol, 1 equiv) in DMF was
added and the reaction mixture was stirred for 48 h at 100 °C. After
cooling to r.t., the mixture was diluted with Et2O. The organic phase
was washed with aq sat. solution of NH4Cl. After drying (MgSO4),
the organic phase was evaporated under reduced pressure and the
residue was purified by column chromatography on silica gel.
2-Phenyl-5H-thiochromeno[3,4-c]pyridine (3d)
Purified by column chromatography on silica gel using CH2Cl2–
EtOAc (1:0 1:1) as eluent; brown oil.
IR (CH2Cl2): 3058, 2942, 1701, 1582 cm–1.
1-Methyl-2-phenyl-5,6-dihydrobenzo[f]isoquinoline (6a)
Purified by column chromatography on silica gel using CH2Cl2–
EtOAc (1:0 1:1) as eluent; brown oil.
IR (CH2Cl2): 3056, 2940, 1695, 1594 cm–1.
1H NMR (250 MHz, CDCl3): δ = 3.89 (s, 2 H, H-5), 7.30–7.34 (m,
3 H), 7.46–7.50 (m, 3 H), 7.89–7.92 (m, 1 H), 7.96 (s, 1 H, H-
1), 8.02 (d, 2 H, J = 7.8 Hz), 8.57 (s, 1 H, H-4).
1H NMR (CDCl3): δ = 2.52 (s, 3 H), 2.81 (m, 4 H), 7.33–7.50 (m, 6
H), 7.56–7.59 (m, 2 H), 7.77–7.80 (m, 1 H), 8.41 (s, 1 H, H-4)
13C NMR (CDCl3): δ = 20.62 (CH3), 26.75(CH2), 29.54 (CH2),
126.04 (CH), 126.44 (C-1), 127.70 (CH), 127.98 (CH), 128.10
(CH), 128.51 (CH), 128.95 (CH), 129.20 (CH), 132.48 (C), 132.74
(C), 140.55 (C), 141.61 (C), 142.85 (C), 145.40 (CH, C-4), 159.84
(C-2).
13C NMR (62.9 MHz, CDCl3): δ = 28.32 (CH2), 116.42 (CH, C-1),
126.07 (CH), 126.57 (C), 126.60 (CH), 126.89 (CH), 128.71 (CH),
128.74 (CH), 128.93 (CH), 129.58 (CH), 132.44 (C), 135.50 (C),
139.29 (C), 142.11 (C), 147.49 (CH, C-4), 157.43 (C-2).
Oximes 4a,b; General Procedure
To a solution of aldehyde 1a,b (2 mmol, 1 equiv) in EtOH (25 mL)
were added NaOAc (4 mmol, 2 equiv) and NH2OH HCl (4 mmol, 2
equiv). The reaction mixture was refluxed for 45 min. After cooling
to r.t., the mixture was extracted with EtOAc. The organic layer was
washed with brine, dried (MgSO4), filtered, and concentrated under
reduced pressure.
1-Methyl-2-phenyl-5H-chromeno[3,4-c]pyridine (6b)
Purified by column chromatography on silica gel using CH2Cl2–
EtOAc (1:0 1:1) as eluent; brown solid; mp 144 °C.
IR (CH2Cl2): 3054, 2965, 1723, 1586 cm–1.
1-Phenylethynyl-3,4-dihydronaphthalene-2-carboxaldehyde
Oxime (4a)
White solid; mp 158 °C.
1H NMR (CDCl3): δ = 2.56 (s, 3 H), 5.03 (s, 2 H, H-5), 7.11–7.17
(m, 2 H), 7.33–7.51 (m, 4 H), 7.57 (d, 2 H, J = 7.2 Hz), 7.87 (dd, 1
H, J = 7.0, 1.3 Hz), 8.40 (s, 1 H, H-4).
IR (CH2Cl2): 3186, 3056, 2936, 1597 cm–1.
13C NMR (CDCl3): δ = 20.22 (CH3), 66.90 (CH2), 117.86 (CH, C-
7), 121.64 (CH, C-9), 122.58 (C), 126.05 (C), 127.11 (C), 127.99
(CH), 128.17 (CH), 128.90 (CH), 129.23 (CH), 130.71 (CH),
137.91 (C), 141.18 (C), 142.66 (CH, C-4), 157.45 (C), 161.42 (C).
1H NMR (250 MHz, CDCl3): δ = 2.71–2.77 (m, 2 H), 2.84–2.88 (m,
2 H), 7.18–7.20 (m, 2 H), 7.27–7.29 (m, 3 H), 7.39–7.40 (m, 2 H),
7.58–7.60 (m, 2 H), 7.80 (d, 1 H, J = 6.8 Hz), 8.71 (s, 1 H, OH).
13C NMR (62.9 MHz, CDCl3): δ = 22.43 (CH2), 26.98 (CH2), 84.91
(C-1′), 98.95 (C-2′), 122.87 (C-3′), 124.29 (C), 126.31 (CH),
126.77 (CH), 127.42 (CH), 128.46 (CH), 128.62 (CH), 128.74
(CH), 131.60 (CH), 132.83 (C), 136.12 (C), 136.62 (C), 151.42
(CH=N).
1-Phenyl-2-methyl-5H-chromeno[3,4-c]pyridine (6b′)
Purified by column chromatography on silica gel using CH2Cl2–
EtOAc (1:0 1:1) as eluent; brown solid; mp 114 °C.
IR (CH2Cl2): 3057, 2977, 1605, 1587 cm–1.
1H NMR (CDCl3): δ = 2.32 (s, 3 H), 5.04 (s, 2 H, H-5), 6.56–6.58
(m, 2 H), 6.98 (d, 1 H, J = 8.1Hz), 7.17–7.20 (m, 3 H), 7.40–7.48
(m, 3 H), 8.35 (s, 1 H, H-4).
5,7-Dimethyl-1-phenylethynyl-3,4-dihydronaphthalene-2-car-
boxaldehyde Oxime (4b)
Brown solid; mp 155 °C.
IR (CH2Cl2): 3243, 3054, 2932, 1596 cm–1.
13C NMR (CDCl3): δ = 24.01 (CH3), 66.61 (CH2), 117.61 (CH, C-
7), 121.23 (CH, C-9), 121.46 (C), 125.76 (C), 127.72 (CH), 128.76
(CH), 129.21 (CH), 129.30 (CH), 130.47 (CH), 131.94 (C), 135.74
(C), 139.12 (C), 143.90 (CH, C-4), 157.23 (C), 157.83 (C).
1H NMR (250 MHz, CDCl3): δ = 2.29 (s, 3 H), 2.35 (s, 3 H), 2.71–
2.75 (m, 4 H), 6.98 (s, 1 H), 7.37–7.40 (m, 3 H), 7.50 (s, 1 H), 7.57–
7.61 (m, 2 H), 8.70 (s, 1 H).
13C NMR (62.9 MHz, CDCl3): δ = 19.29 (CH3), 21.08 (CH3), 22.26
(CH2), 22.63 (CH2), 84.70 (C-1′), 98.53 (C-2′), 123.00 (C-3′),
124.70 (C), 125.04 (CH), 128.42 (CH), 128.61 (CH), 131.37 (C),
131.51 (CH), 131.56 (CH), 132.53 (C), 134.66 (C), 135.44 (C),
136.06 (C), 151.45 (CH = N)
1-Methyl-2-phenyl-5H-thiochromeno[3,4-c]pyridine (6c)
Purified by column chromatography on silica gel using CH2Cl2–
EtOAc (1:0 1:1) as eluent; brown oil.
IR (CH2Cl2): 3057, 2972, 1685, 1587 cm–1.
1H NMR (CDCl3): δ = 2.43 (s, 3 H), 3.75 (s, 2 H, H-5), 7.29–7.32
(m, 2 H), 7.38–7.50 (m, 3 H), 7.55–7.59 (m, 3 H), 7.76–7.80 (m, 1
H), 8.47 (s, 1 H, H-4)
Synthesis 2003, No. 5, 717–722 ISSN 0039-7881 © Thieme Stuttgart · New York

722
S. Hesse, G. Kirsch
PAPER
(6) (a) Larock, R. C.; Zhang, H. Org. Lett. 2001, 3, 3083.
13C NMR (CDCl3): δ = 20.71 (CH3), 30.59 (CH2), 125.36 (CH),
127.20 (C), 127.99 (CH), 128.19 (CH), 128.62 (CH), 129.17 (CH),
129.48 (CH), 130.45 (CH), 130.49 (C), 132.77 (C), 137.71 (C),
141.20 (C), 142.86 (C), 143.72 (CH, C-4), 160.75 (C-2)
(b) Larock, R. C.; Roesch, K. R.; Zhang, H. J. Org. Chem.
2001, 66, 8042.
(7) (a) Huang, Q.; Hunter, J. A.; Larock, R. C. Org. Lett. 2001,
3, 2973. (b) Dai, G.; Larock, R. C. Org. Lett. 2001, 3, 4035.
(8) Hesse, S.; Kirsch, G. Synthesis 2001, 755.
(9) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett.
1975, 4467.
(10) (a) Jeffery, T. J. Chem. Soc., Chem. Commun. 1984, 1287.
(b) Nguefack, J. F.; Bolitt, V.; Sinou, D. Tetrahedron Lett.
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(11) Kanekyio, N.; Kuwada, T.; Choshi, T.; Nobuhiro, J.; Hibino,
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(12) Arnold, Z.; Zemlicka, J. Collect. Czech. Chem. Commun.
1959, 24, 2385.
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Synthesis 2003, No. 5, 717–722 ISSN 0039-7881 © Thieme Stuttgart · New York